Inflammatory Breast Cancer: Diagnosis and Treatment
By Richard E. Blair, DO, MPH
Impressive progress has been made in the past twenty years in the treatment of breast cancer. Morbidity and mortality both have seen remarkable decreases. Advances in breast cancer survival can be attributed to a greater public awareness of the incidence of breast cancer, improved screening techniques, utilization of mammograms, and advancement in surgical, medical, hormonal, and radiation therapies.
Researchers have gained insight into the genetic basis of breast cancer, allowing those at highest risk for developing carcinoma of the breast to be more readily identified. However, Inflammatory Breast Cancer (IBC), although rare, remains an elusive disease; difficult to diagnose, aggressive in nature, and often advanced when definitively diagnosed.
Although uncommon, IBC is exceedingly dangerous. Its epidemiology, clinical presentation, diagnosis, and treatment differs markedly from other forms of breast carcinoma IBC may present quickly and advance rapidly.
Once diagnosed, IBC is frequently at Stage 3 or 4A, making treatment and cure all the more challenging. Coupled with its aggressive nature, IBC carries greater morbidity and mortality when compared to other types of breast cancer. It is considered to be the deadliest form of breast disease. Consequently, a diagnosis of IBC necessitates an expeditious approach to chemotherapy, surgery, radiation therapy, and possible hormonal therapy.
The purpose of this article is to review the unique nature of IBC; its epidemiology, genetics, clinical presentation, and diagnosis. Also, surgical, intervention radiation therapy, and chemotherapy will be addressed. Last, future therapeutic management developments of IBC will be discussed.
Epidemiology
Women in the United States have a 13 percent chance of developing breast cancer within their lifetime.1 Numerically, 213,000 new cases of breast cancer were diagnosed in the U.S. in 2006. Of those new cases, approximately 5 percent were IBC.2 IBC may present in woman of younger age than does non-IBC, further compounding its definitive diagnosis.3 In a retrospective cohort study, the mean age of 153 patients diagnosed with IBC was 53 years.4
In an additional study of IBC conducted between 1988 and 1997, several statistically significant trends were noted. The study involved 3648 cases. In the time period studied, IBC incidence rates rose from 2.0 to 2.5 case per 100,000 woman-years (P<.001), IBC incidence rates were statistically higher in black women (3.1 cases per 100,000 woman years) as compared to white woman (P<.001). and a diagnosis of IBC carried with it a poorer survival rate than locally advanced breast cancer (LABC) (P<.001). Median survival for those woman diagnosed with IBC was 2.9 years as opposed to 6.4 year survival rate for those diagnosed with LABC, ( P<.0001). Also, black women with IBC had poorer survival rate than white women (P<.001).5
Pathophysiology
Histoligically, IBC is marked by sheets of invasive mammary carcinoma cells with dermal lymphatics blocked by tumor cells, resulting in an increase in tissue lymphatic pressure. Inflammation ensues. Biopsy performed of the affected tissue will demonstrate extensive lymphovascular invasion by tumor emboli involving the superficial dermis vessels.6
No particular histologic variety of breast cancer is associated with IBC. IBC may manifest in the presence of infiltrating ductal, lobular, medullary, or large cell carcinomas.7 Primary IBC is often of the ductal type with prominent angiolymphatic invasion characterized by pleomorphic tumor cells and highly atypical mitotic figures. Regardless of carcinoma type, the main feature of IBC is infiltration of the dermal lymphatics, resulting in increased lymphatic pressure and inflammation. Edema and erythematic ensue. IBC is highly antigenic and angioinvasive.
Skin biopsy should be performed whenever a clinical suspicion of IBC exists. Pathology will usually, but not always, reveal lymphatic invasion by tumor emboli involving the superficial dermal plexus in the papillary and reticular dermis. The absence of lymphatic invasion on biopsy does not exclude the diagnosis of IBC.8
Diagnosis and Presentation
Diagnosis of IBC is primarily made on the clinical grounds established by Haagensen: diffuse erythema, edema involving greater than two thirds of the breast, peau d’ orange, tenderness, induration, warmth, and enlargement.9
Many patients exhibit axillary adenopathy with distant metastasis upon presentation. Thus the designation “Inflammatory Breast Cancer” originates primarily from the appearance of the affected breast. The breast may be swollen to twice its normal size and profoundly painful.
Unfortunately, the described diagnosis may often lead to an initial diagnose of mastitis, further delaying treatment for IBC. If mastitis is suspected, a two week course of antimicrobrial therapy targeted to methicillan resistant organisms is prudent. If symptoms fail to resolve, the patient must be referred to a breast surgeon for biopsy based on suspicion of IBC. Radiologically, less than one half of IBC cases will demonstrate a discrete mass on mammography.10 Additionally, breast ultrasound may also fail to yield an identifiable lesion.
Prognosis
IBC is the most lethal form of breast cancer. At the time of presentation, many patients will demonstrate advanced disease with distant metastasis. For those diagnosed with IBC, the most important prognostic indicator is the extent of lymph node involvement. Patients with no lymph node involvement at time of diagnosis may expect a longer rate of survival. Also, those patients with estrogen receptor negative carcinoma have been identified as having a poorer outcome.
Unfortunately, 30 percent of IBC patients have distant metastasis to the brain, bones, and liver at time of definitive diagnosis.11 In decades past, IBC therapy consisted of mastectomy followed by chemotherapy. The outcome continued to be grim; the five year survival rate is 15 percent.12 The current standard of care for those diagnosed with IBC consists of chemotherapy, followed by mastectomy, axillary lymph node dissection, local radiation therapy, and hormonal therapy when indicated.13 In spite of the multiple modality approach of chemotherapy, surgery, radiation, and hormonal therapy, the long term survival for those diagnosed with IBC remains unfavorable. The three year survival rate is approximately 40 percent for those with IBC, versus a five year survival rate of 85 percent for those with non-IBC breast carcinoma. 14
Hormone Receptor Status
About two thirds of non-IBC breast cancer are positive for estrogen or progesterone receptors. Consequently, hormone receptor blocking agents such as tamoxifen may be used to treat breast cancer and breast cancer metastasis. Also, breast cancer survivors are treated post operatively with tamoxifen and similar hormone receptor blockers.
Doing so has been found to increase survivability in those with breast cancer and decrease re-occurrence. Tamoxifen therapy is often used to treat women with a strong family history of breast cancer in hopes of prevention. Unfortunately, IBC more often than not is hormone receptor negative. Sixty percent of IBC tissue samples lack hormone receptor expression.15 The unique hormonal characteristics of IBC render it all the more dangerous.
Genes Involved in IBC
The rapid onset of symptoms, early metastatic spread, and intense inflammatory properties of IBC have lead investigators to search for genetic factors which may be responsible to its aggressive nature. Thus far,
researchers have failed to identify definitive levels of IBC specific cytokines and inflammatory factors which may be responsible for the aggressive nature of IBC.16
Medical and Surgical Therapies
Proper management of IBC is a multidisciplinary task. Early diagnosis via clinical suspicion followed by biopsy is vital. Consultation with a medical oncologist, breast surgeon or surgical oncologist, and radiation oncologist is imperative. Neoadjuvant therapy is the first step in the proper management of IBC. Chemotherapeutic agents used in the treatment of IBC include: 5-fluorouracil, doxorubicin, cyclophasphamide, methotrexate, vincristine, vinblastine, prednisone, taxane, paclitaxil, etoposide.17
All have been used preoperatively with a varying degree of success. If a clinical response is attained with chemotherapy, surgery follows. Surgical treatment consists of a modified radical mastectomy followed by axillary lymph node dissection. Lymph node dissection is carried out for staging purposes and to identify hormone receptor positive tissue.
The radical modified mastectomy procedure is the most common surgical approach to advanced breast cancer. It consists of removal of breast, breast tissue, axillary nodes, and occasionally the pectoralis minor. However, the pectoralis major is spared. Doing so leaves the chest wall intact and allows for future breast reconstructive surgery. Following surgery, local radiation therapy is indicated. Last, hormonal therapy may be called for dependent on hormonal receptor status the biopsied tissue.
Future Therapies
Although significant progress has been made in last several decades, much remains unknown about the genetic etiology of IBC. Various genetic mutations are associated with a greater likelihood of IBC. Also, a number of different genetic expressions have been identified in IBC patients with good, intermediate, and poor outcomes. Consequently, it is postulated that IBC may be a disease entity which manifests as the synergistic end result of more than one genetic identifier.
Comprehensive molecular analysis of IBC may assist in identifying future novel approaches to genetic therapy which may prove beneficial.18 Many clinical investigations are underway in search of new chemotherapeutic agents which may be successful in the management of IBC. Combination regimens that include angiogenic modifiers combined with a variety of chemotherapeutic agents have shown limited promise. Future biological targets in IBC treatment research include oncogenes, tumor suppressor genes, and angiogenic modulators.19
Targeted Therapies
The novel approach of targeted therapies has developed over the past ten years. As opposed to typical chemotherapy, which targets all rapidly growing cells, targeted therapy identifies neoplastic cells and targets particular cellular processes vital to the proliferation of the malignant cell. For example, typical chemotherapies are quite cytotoxic, and cannot discern between healthy and malignant cells.
Consequently, traditional chemotherapy is associated with the side effects of alopecia, nausea and vomiting, and immune suppression. Targeted therapy, however, involves the use of monoclonal antibodies and small molecule inhibitors to block specific steps in cancer cell formation. Targets include particular intracellular processes or cell wall receptor blockade. Breast, colon, lung, and pancreatic cancers as well as leukemia, lymphoma, and multiple myeloma are being treated with targeted therapy, all with some success. Targeted therapy may be used alone or in combination with traditional chemtherapies.
Traztuzimad (Herceptin) and Lapatinib (Tykerb) are two targeted therapies presently in use for treatment of breast cancer. Advantages of targeted therapies include ease of administration, often via the oral route, and decreased toxicity. Unfortunately, targeted therapies are prohibitively expensive. Undoubtedly, the price of targeted therapies will decrease as their use increases.
The Role of the Family Physician
IBC is a complex, poorly understood, aggressive, and most often fatal disorder. Consequently, management of those diagnosed with IBC involves upwards of half a dozen specialists. The family physician may often find himself as the only provider the patient may turn to during the dizzying array of appointments and treatments which accompanies management of any serious illness; especially one which carries such a poor prognosis as does IBC.
Frequently, the family physician is the cancer patient’s sole reference for continuity during management of a disease process which involves a multitude of providers.
Treatment of IBC involves therapies and modalities which render the patient psychologically and physically devastated. Depression, anxiety, profound and irretraceable nausea and vomiting are just a few of the side effects accompanying management of IBC. Consequently, the family physician must be familiar with the latest treatment options available in management the side effects of IBC therapy.
In addition to tending to the needs of the patient, the family physician must frequently care for the spouse, children, and extended family affected by the disease. A close working relationship with the many specialists involved in management of IBC is imperative. Last, the family physician is frequently the sole provider for end of life issues and care for the terminally ill. Up to date knowledge of the latest pharmacologic trends regarding pain control end of life issues is a must.
Conclusion
IBC, although rare, is the most aggressive and deadly form of breast cancer. Timely diagnosis is of the utmost importance. Consequently, the family physician must be aware of the early manifestations of IBC and the urgency involved in its proper management Expeditious referral to team of experienced specialist is paramount. Under the best of circumstances, a diagnosis of IBC carries with it a poor outlook. At worst, it can be rapidly fatal in a matter of several months. Consequently, the astute family physician must be familiar with the presentation, diagnosis, therapy, and complications of IBC.
Dr. Blair is a 1996 graduate of KCOM. He was certified in Family Medicine in 2000. He is currently at Lt. Col. In the U.S. Air Force and serves as a Family Physician/Flight Surgeon at Naval Air Station, Whiting Field, Milton, Florida.
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